+Open data
-Basic information
Entry | Database: PDB / ID: 8u7h | ||||||
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Title | Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915 | ||||||
Components | non-specific serine/threonine protein kinase | ||||||
Keywords | HYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
Function / homology | Function and homology information GTP-dependent protein kinase activity / regulation of signal transduction / protein autophosphorylation / cell differentiation / non-specific serine/threonine protein kinase / protein phosphorylation / GTP binding / ATP binding / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||
Authors | Zhu, H. / Sun, J. | ||||||
Funding support | United States, 1items
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Citation | Journal: Cell Discov / Year: 2024 Title: Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. Authors: Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun / Abstract: LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being ...LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8u7h.cif.gz | 201.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8u7h.ent.gz | 148 KB | Display | PDB format |
PDBx/mmJSON format | 8u7h.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8u7h_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8u7h_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8u7h_validation.xml.gz | 40.8 KB | Display | |
Data in CIF | 8u7h_validation.cif.gz | 60.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/u7/8u7h ftp://data.pdbj.org/pub/pdb/validation_reports/u7/8u7h | HTTPS FTP |
-Related structure data
Related structure data | 41982MC 8fo7C 8u7lC 8u8aC 8u8bC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 136843.469 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2 / Production host: Homo sapiens (human) / References: UniProt: Q17RV3 |
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#2: Chemical | ChemComp-GDP / |
#3: Chemical | ChemComp-A0T / [ |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: LRRK2-GNE-7915 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 137 kDa/nm / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 62.08 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software |
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CTF correction | Type: NONE | ||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95644 / Symmetry type: POINT |